Abstract
Hyperlipidemia, a syndrome characterized by an abnormal elevation of blood lipids, causes chronic lethal metabolic disorders. Although statins are regularly prescribed to patients, an alternative to treat the burden of excessive lipids is required for cholesterol control. In this study, it was found that the treatment of casein hydrolyzed by pepsin and trypsin induced trans-intestinal cholesterol excretion (TICE) through ATP-binding cassette subfamily G members 5 (ABCG5) expression. Next, we analyzed sequences of the peptides responsible for TICE induction, synthesized artificial peptides based on the sequences, and the hypolipidemic effects of the peptide treatments were assessed in both in vitro and in vivo models. We determined that two bioactive peptides contained in casein hydrolysates (SQSKVLPVPQK and HPHPHLSF) induced TICE through the expression of ABCG5 in enterocytes and suppressed hepatic mRNA expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) and CYP8B1by ileal FGF19 expression both in an liver X receptor α (LXRα)-mediated manner. In the hyperlipidemic mouse models, the oral administration of peptides reduced serum cholesterol levels through elevation of the ABCG5 expression in proximal intestine and fecal cholesterol secretion. Besides this, peptides induced ileal expression of fibroblast growth factor 15/19 (FGF15/19) and inhibited hepatic bile acid synthesis. We found that the oral treatment of casein-derived bioactive peptides could improve hyperlipidemia by regulating intestinal excretion and hepatic synthesis of cholesterols.
Highlights
Hyperlipidemia, an abnormal elevation of lipids such as triglyceride, cholesterol, and low-density lipoprotein (LDL) in the blood, is a global metabolic syndrome
We found that the oral treatment of casein-derived bioactive peptides could improve hyperlipidemia by regulating intestinal excretion and hepatic synthesis of cholesterols
Antibodies against ATP-binding cassette subfamily G members 5 (ABCG5) and ABCG8 were purchased from Abcam (Cambridge, MA, USA) and those against FGF15, fibroblast growth factor 19 (FGF19), and α-tubulin were purchased from Santa
Summary
Hyperlipidemia, an abnormal elevation of lipids such as triglyceride, cholesterol, and low-density lipoprotein (LDL) in the blood, is a global metabolic syndrome. The causes of hyperlipidemia remain elusive, some autosomal mutations in genes involved in lipoprotein catabolism, including LDL receptor (LDLR), apolipoprotein B, proprotein convertase subtilisin/kexin type 9 (PCSK9), and upstream transcription factor 1, are reportedly related with primary hyperlipidemia [1]. LDL clearance and LDLR expression are often inactive and hepatic lipid accumulation is elevated, further inducing blood cholesterol accumulation through hepatic very-low-density lipoprotein production [2]. Hyperlipidemia is an important risk factor leading to secondary metabolic diseases such as type 2 diabetes, obesity, and non-alcoholic fatty liver disease and cardiovascular diseases such as arteriosclerosis and myocardial infarction. Weight loss and an improvement in body mass index (BMI) could suppress hyperlipidemia and its related disorders; the need for strategies to alleviate excessive blood lipids is urgent.
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